Predictors and biomarkers of Alzheimer's Disease (AD) and other neurodegenerative diseases In collaboration with Dr. Ed Goetzl from UCSF and other investigators, we developed a methodology for isolating blood exosomes and enriching them for neuronal origin by immunoprecipitation using neuronal surface marker L1CAM or enriching them for astrocytic origin by immunoprecipitation using astrocytic surface marker GLAST. To date, we have conducted several case control studies measuring exosomal beta-amyloid, tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, complement and other proteins, in AD and control subjects. We have found highly significant differences that, for some proteins, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. I have published several manuscript on the topic (in the journals JAMA Neurology (twice), Journal of Alzheimer's disease, Journal of Neurovirology, Brain Injury, Alzheimer's and Dementia, FASEB J (seven times), Neurology, Annals of Neurology, Annals of Clinical and Translational Neurology, Frontiers in Neuroscience, and WIRES RNA). This last year, we showed that exosome biomarkers predict cognitive decline and future AD diagnosis in a large preclinical cohort from the BLSA. In addition, we showed that exosome biomarkers predict treatment response and show target engagement in clinical trials of metabolic interventions in AD (intranasal insulin) and PD (exenatide). One major goal for the coming year is to complete and publish studies of exosomal markers in diagnosis of AD in large preclinical/early clinical cohorts, such as the JH ADRC, the Wisconsin Registry for Alzheimer's Prevention and Atherosclerotic Risk in Communities. These cohorts are ideal for assessing longitudinal changes in these markers and their potential to predict AD at the preclinical stage, disease progression and conversion from MCI to AD. In addition we will validate exosome biomarkers against CSF biomarkers, amyloid and tau PET and brain pathology leveraging ante-mortem samples and brain autopsy findings available to the JH ADRC. Finally, we will try to combine RNA with protein exosome biomarkers to further improve diagnostic performance. In addition to a main focus on AD, I am conducting exosome biomarker studies in vascular cognitive impairment/vascular dementia, Parkinson's disease (e.g. response to exenatide), Lewy Body disease, Multiple Systems Atrophy, Traumatic Brain Injury, Restless Legs Syndrome (e.g. showing increased exosome ferritin in neuronal exosomes in the disease), and Multiple Sclerosis. In addition, I have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. In a case-control study of patients with MCI/AD and healthy volunteers published in the Annals of Clinical and Translational Neurology, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted several studies on autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. In addition, the ability to generate future events was associated with Frontal Lobe functions. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are both impaired in AD. In addition, we published a study on minimal interference in AD, a review of hallucinations in AD, and a study on olfaction in AD. Clinical studies in cognitive aging/prevention of cognitive decline I am conducting a study of Intermittent caloric restriction (CR)implementing 5-2 CR (alternating 5 days of regular calorie intake and 2 days of CR). This is a 8-week study of 5-2 CR in overweight middle aged subjects to assess potential beneficial effects on insulin resistance, brain metabolism, cognitive performance, fMRI activity and biomarkers. If this study is positive, 5-2 CR may be a candidate intervention for primary prevention of AD at midlife. I am in collaboration with Investigators at McGill University, Canada, who plan to start a clinical trial of intranasal insulin in the peri-operative period of heart surgery patients to prevent post-operative cognitive decline. Our main goal is to conduct exosome biomarker analysis showing response to intranasal insulin.